This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autolgous transplantation for myeloma improves survival, but the immunologic mechanisms accounting for this improvement are unknown. Our data indicate that NKG2D+CD8+T cells may be one reason for this benefit. NKG2D, one of four NK activating receptors, has been identified on some CD8+T cells that mediate TCR-independent and non-MHC restricted tumor cell killing. Since the NKG2D receptor recognizes ligands expressed on myeloma cells, these NKG2D+CD8+T cells aggressively kill myeloma cells and provide a unique immunotherapy opportunity. Immune mobilization, using IL-2 and growth factors (i.e. stimulation of hematopoietic cells into the blood that can be used for transplant) expands CD8+T cytotoxic cells that acquire the NKG2D receptor and perform their killing using NKG2D. We have identified an increase number and function of NKG2D+CD8+T cells in vivo early post-transplant. When murine CD8+T cells are transduced with a chimeric NKG2D receptor and injected into myeloma-bearing mice, 100% of the mice survive. We hypothesize that the infusion of immune mobilized cells into myeloma patients as part of the transplanted cells will markedly enhance immune reconstitution, by increasing the number and function of NKG2D+CD8+T cells. These proposed studies will define the presence, function and mechanisms of NK cell activating receptors on recovering CD8+T cells in vivo following transplant. Our long-term hypothesis is that this regimen will improve survival by enhancing early immune recovery following transplantation.